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The formation of neurotoxic aggregates by amyloid-β peptide (Aβ) is considered to be a key step in the onset of Alzheimer's disease. It is widely accepted that oligomers are more neurotoxic than amyloid fibrils in the aqueous-phase aggregation of Aβ. Membrane-mediated amyloidogenesis is also relevant to the pathology, although the relationship between the aggregate size and cytotoxicity has remained elusive. Fluorescence correlation spectroscopy (FCS) is a sensitive method to monitor molecular aggregation processes by measuring diffusion of fluorophore-labeled molecules. Here, we monitored the initial aggregation process of Aβ on cell membranes of SH-SY5Y neuroblastoma cells. For example, aggregation of Aβ-(1-42) was evaluated by using Aβ-(1-42) (5 μM) doped with fluorophore-Aβ-(1-42) (10 nM). A membrane-bound Aβ component was detected in FCS autocorrelation curve after 1-h incubation of the Aβs with the cells. Following incubation for 10 h, Aβ-(1-42) formed oligomers composed of 10 Aβ molecules. These Aβ oligomers formed on membranes did not induce activation of caspase-3, an effector caspase for apoptosis, therefore were not neurotoxic, in contrast to reported Aβ oligomers prepared in aqueous phase. Formation of larger Aβ fibrils on membranes was found to be critical for Aβ neurotoxicity. We also report that trace amounts of pyroglutaminated Aβ-(3-42), a minor species of Aβ, can enhance initial aggregation process of Aβ-(1-42) on the cell membranes. These results indicate the usefulness of FCS detection of small Aβ oligomers formed on cell surface, which can act as pathogenic seeds for amyloid fibrils responsible for neurotoxicity.

Cell-surface Initial Aggregation Process of Amyloid-β Peptides Studied by Fluorescence Correlation Spectroscopy